Human immunodeficiency virus (HIV-1) renders the host susceptible to a variety of serious central nervous system (CNS) diseases such as AIDS dementia complex and HIV-1 encephalopathy. The use of highly active antiretroviral therapy (HAART), including protease inhibitors, has been effective in slowing the spread of the virus, however, drug resistant tissue reservoirs, such as the brain, remain. Treatment of HIV-1 in the brain has been hampered by the fact that nucleoside drugs do not penetrate the blood-brain barrier (BBB) well and newer treatments, i.e., protease inhibitors, also have very limited delivery to the brain. One component of the BBB that limits delivery of HAART into the CNS is the membrane-bound drug efflux pumps, such as p-glycoprotein (P-gp) and multidrug resistance-associated proteins (MRPs). Recently, it has been shown that both nucleosides and protease inhibitors are substrates for efflux transporters. The long-term objective of this research is to develop better therapeutic strategies to enhance the targeted delivery of antiretroviral drugs to the CNS by using novel drug delivery systems, such as polymeric carriers (Pluronics). Our hypothesis is that novel drug delivery systems will enhance the brain distribution and CNS targeting of HAART and therefore improve efficacy. The specific aims to test this hypothesis are: 1) examine the effect of Pluronics on the interactions of various antiretrovirals with isolated P-gp membranes using photoaffinity labeling and P-gp ATPase assay, 2) study the effects of Pluronics on the transport properties of antiretroviral drugs in the in vitro BBB and efficacy in infected target cells, i.e., monocytes/macrophages, and 3) determine the effect of this novel drug delivery technology on the brain distribution of antiretrovirals in vivo characterizing the efficacy of the most promising formulations in an HIV-infected SCID mouse model of HIV- encephalopathy. The current proposal examines the CNS targeting of HAART in both in vitro and in vivo models of the blood-brain barrier, and the efficacy of that targeted drug delivery. New approaches to improve brain penetration of anti-HIV drugs will be valuable in the treatment of HIV-encephalopathy and in eradicating the virus from potential sanctuary sites.